DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-2, 14, 20, 23, 25-26, 35, 41-42, 54, 56, 66-67, 69-71, 73, and 78-79 are pending.
Claims 35, 41-42, 54, 56, 66-67, 69-71, 73, and 78-79 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected group, there being no allowable generic or linking claim. Applicant timely traversed the restriction requirement in the reply filed on 4/17/2026.
Election/Restrictions
Applicant's election with traverse of the restriction requirement of 2/25/2026 in the reply filed on 4/17/2026 is acknowledged. The traversal is on the ground(s) that the claims as amended share a common technical feature that is not disclosed in the prior art. This is not found persuasive because the cell of claim 1 is obvious in view of Nagata and Dezfulian as described below.
The requirement is still deemed proper and is therefore made FINAL.
Claim interpretation
Claim 1 is interpreted as being directed to a cell comprising effectively two alternative types of reporter comprising scramblases where either:
The scramblase does not comprise a caspase cleavage site that activates it. Effectively a serine protease (potentially granzyme) must be the trigger.
The scramblase comprises a caspase and/or a serine protease cleavage site, which activate the scramblase when either or both are cleaved. The reporter then further comprises an additional, separate reporter which reports contact with cytotoxic lymphocytes.
In other words, the scramblase may comprise a caspase and/or a serine protease cleavage site, but if the scramblase comprises a caspase cleavage site it must further comprise an additional reporter of contact with cytotoxic lymphocytes.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Nagata and Dezfulian
Claims 1, 2, 14, 20, 23, 25, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over:
Nagata (US20150301024A1) (Provided in IDS of 8/3/2023)
Dezfulian (WO2018227091A1)
Regarding claim 1, Dezfulian teaches methods and reagents for identifying target antigens specific to T cells, such as cytotoxic T cells. (Dezfulian [0002]). Dezfulian teaches an antigen presenting cell (APC) comprising an exogenous nucleic acid encoding candidate antigen, and a molecular reporter of granzyme B activity. (Dezfulian [0004]). Dezfulian's molecular reporter of GzB activity comprises a fusion polypeptide comprising a GzB cleavage site linked to a "detection molecule", and teaches that this reporter molecule could be one of many types of reporter molecule, including a cell surface detectable-based reporter of GzB activity. (Dezfulian [0005]).
Dezfulian also teaches that to detect GzB activity, they modified an existing reporter designed to detect the activity of caspases and of the TEV protease. (Dezfulian [00203]). So, Dezfulian suggests that existing reporters that are cleaved by caspases may be modified to instead detect cleavage by another enzyme, including specifically granzyme B activity.
Dezfulian does not specifically teach that the cell surface detectable-based reporter of GzB activity is a scramblase, or that the resulting cell surface signal protein is Phosphatidylserine (PtdSer).
Nagata teaches a method of screening for a modulator of Xkr8 (a naturally-occuring scramblase), comprising contacting Xkr8-expressing cells with candidate modulators, and then observing resulting changes in distribution of a phospholipid in the plasma membrane of the cells (Nagata, Abstract). Nagata's invention is directed to screening candidate modulators of the cleavage of Xkr8 with caspase (Nagata [0043]), which Nagata describes as being useful to develop therapeutic agents for apoptotic diseases. (Nagata, [0051]).
Nagata's cells comprise an hXkr8 scramblase (Nagata [0005]) which naturally comprises a caspase cleavage site, which when cleaved by a caspase, results in the presentation of Phosphatidylserine (PtdSer) on the surface of the cell, acting as a reporter that the caspase has been cleaved (Nagata [0042, 0024-31]). Nagata then teaches that when Xkr8-expressing cells are treated with fluorescently-labelled AnnexinV, the amount of AnnexinV bound to the cell surface is measured, which reports the cleavage of the caspase cleavage site. (Nagata, [0047]).
So, Dezfulian teaches methods and reagents for identifying target antigens specific to cytotoxic lymphocytes, wherein the reporter comprises a granzyme B cleavage site, and that the reporter may further comprise a cell surface detectable-based reporter. Dezfulian also teaches that previously known reporters of caspase activity have been re-engineered to comprise a granzyme B cleavage site in order to report GbZ activity.
Nagata teaches a useful cell surface detectable reporter which comprises scramblase comprising a caspase cleavage site, hXkr8, which effectively reports the activity of caspase in a cell by causing PtdSer to be presented on the outside of the cell, which is readily detectable with fluorescently-labelled AnnexinV.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to use Nagata’s cell surface reporter protein as the reporter protein in Dezfulian’s cell. One of ordinary skill in the art would have been motivated to do so, since Nagata teaches a useful reporter protein, hXkr8, but is using it to detect caspase cleavage instead of cleavage by granzyme B. Dezfulian teaches a method of screening candidate epitopes in T cells by using a reporter molecule sensitive to granzyme B, and suggests the use of a range of reporter proteins as part of their invention. Dezfulian also teaches that other reporter proteins used to report caspase cleavage may be modified to report granzyme B cleavage instead. So, the skilled artisan would be motivated to modify Nagata’s scramblase reporter to have a granzyme B cleavage site (serine protease cleavage site), and use it as the reporter protein in Dezfulian’s cell in order to predictably produce a cell that signals granzyme B exposure by presentation of Phosphatidylserine (PtdSer).
One of ordinary skill in the art would have had a reasonable expectation of success, since Dezfulian suggests the re-purposing of caspase reporters to granzyme B reporters, and Nagata teaches that their hXkr8 is a useful reporter protein.
Regarding claim 2, Nagata's hXkr8 scramblase promotes the translocation of PS to the outer leaflet of a cell membrane lipid bi-layer after cleavage by the caspase (Nagata [ 0025 ]).
Regarding claim 14, Dezfulian teaches that In various embodiments, the molecular reporter of GzB activity comprises a fusion polypeptide comprising a GzB cleavage site linked to a detection molecule, such as wherein the molecular reporter comprises a modified infrared fluorescent protein, a membrane tethered CRE recombinase, an antibody- based reporter of GzB activity, an ER retention-based reporter of GzB activity, a cell surface detectable-based reporter of GzB activity, or combinations thereof. (Dezfulian [0005]). That is, Dezfulian teaches that multiple different reporters of GzB activity may be used in their cell/method.
Regarding claim 20, Dezfulian teaches that their cell comprising the GbZ reporter protein may be a primary cell or a cell of a cell line. (Dezfulian [0005]).
Regarding claim 23, Dezfulian teaches that their cell comprises an exogenous inhibitor of caspase-activated deoxyribonuclease (CAD)-mediated DNA degradation, a CAD knockout, or a caspase knockout (e.g., caspase 3 knockout). (Dezfulian [0004]).
Regarding claim 25 and 26, Dezfulian teaches that their cell comprises an exogenous nucleic acid encoding one or more candidate antigens wherein the one or more candidate antigens are expressed and presented with MHC class I or MHC class II molecules. (Dezfulian [0004]).
Conclusion
Claims 1, 2, 14, 20, 23, 25, and 26 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to THOMAS RUSSE AMICK whose telephone number is (571)272-5474. The examiner can normally be reached 7:30-5 M-F.
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/THOMAS R. AMICK/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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